(i) Field of the Invention
The present invention relates to novel pyrimidinedione derivatives and acid addition salts thereof, to methods of preparing the same, and to pharmaceutical agents containing the same which are effective for the treatment of arrhythmia.
(ii) Description of the Related Art
The mechanism of the occurrence of arrhythmia is complicated. Abnormalities in stimulation production and disorders in the conducting system or combinations thereof are considered to be responsible.
As to disorders in excitation conduction, the reentry theory is representative.
One of the conditions of occurrence of arrhythmia is irregularity in the refractory period in various parts of the heart. In addition, one-directional block, shortened refractory period, delay in conduction and the presence of circus movement are complicatedly involved.
Heretofore, various antiarrythmic agents have been used for the treatment of arrhythmia.
The antiarrythmic agents are classified into four groups according to their modes of action.
That is, E. M. Vaughan Williams (Vaughan Williams E. M.; "Advances in drug research, Vol. 9", ed. by Harper N. J., Simmonds A. B., Academic Press, London, 1974, pages 69-101) have classified the antiarrythmic agents into the following four groups in accordance with their actions against the action potential of cardiac muscle or against the ionic current which generates the action potential.
Class I: Sodium channel depressors
These agents are efficacious in repressing a sodium current. However, they have no or only minute effects on the retention time of the normal action potential and decrease the maximum rising velocity (V.sub.max) of the sodium current. The antiarrythmic agents which belong to this class have a high antiarrythmic activity but at the same time strongly repress cardiac functions. Careful consideration is required in administering to patients with cardiac failure or hypotension.
Class II: Beta-blocking agents
The agents in this class, represented by propranolol, are efficacious in the beta-blocking action and are useful in treating patients with arrhythmia in which the sympathetic nerve is involved. However, the care must be taken for use since these agents have side-effects caused by the beta-blocking action, such as depression of cardiac functions, induction of bronchial asthmatic attack and hypoglycemic seizures.
Class III: Pharmaceutical agents for prolonging the retention time of the action current.
These agents are efficacious in remarkably prolonging the retention time of the action current of the cardiac muscle and in prolonging an effective refractory period. Re-entry arrhythmia is considered to be suppressed by the action of the pharmaceutical agents of Class III. The medicaments of this Class III include aminodarone and bretylium. However, all the agents have severe side effects, and therefore, careful consideration is required for use.
Class IV: Calcium antagonists
These agents control a calcium channel and suppress arrhythmia due to automatic sthenia of sinoatrial nodes and to ventricular tachycardia in which atrial nodes are contained in the re-entry cycle.
Among these antiarrythmic agents, pharmaceutical agents of the Class III type are considered to be particularly important and most efficacious, and known to be effective on ventricular arrhythmia which is most fatal.